RESUMO
The B-cell receptor (BCR) and its immature form, the precursor-BCR (pre-BCR), have a central role in the control of B-cell development, which is dependent on a sequence of cell-fate decisions at specific antigen-independent checkpoints. Pre-BCR expression provides the first checkpoint, which controls differentiation of pre-B to immature B-cells in normal haemopoiesis. Pre-BCR signalling regulates and co-ordinates diverse processes within the pre-B cell, including clonal selection, proliferation and subsequent maturation. In B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), B-cell development is arrested at this checkpoint. Moreover, malignant blasts avoid clonal extinction by hijacking pre-BCR signalling in favour of the development of BCP-ALL. Here, we discuss three mechanisms that occur in different subtypes of BCP-ALL: (i) blocking pre-BCR expression; (ii) activating pre-BCR-mediated pro-survival and pro-proliferative signalling, while inhibiting cell cycle arrest and maturation; and (iii) bypassing the pre-BCR checkpoint and activating pro-survival signalling through pre-BCR independent alternative mechanisms. A complete understanding of the BCP-ALL-specific signalling networks will highlight their application in BCP-ALL therapy.
Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Receptores de Células Precursoras de Linfócitos B/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/prevenção & controle , Animais , Humanos , Receptores de Células Precursoras de Linfócitos B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismoRESUMO
Inhibitors of B-cell receptor (BCR) and pre-BCR signaling were successfully introduced into patient care for various subtypes of mature B-cell lymphoma (e.g., ibrutinib, idelalisib). Acute lymphoblastic leukemia (ALL) typically originates from pre-B cells that critically depend on survival signals emanating from a functional pre-BCR. However, whether patients with ALL benefit from treatment with (pre-) BCR inhibitors has not been explored. Recent data suggest that the pre-BCR functions as tumor suppressor in the majority of cases of human ALL. However, a distinct subset of human ALL is selectively sensitive to pre-BCR antagonists.
Assuntos
Terapia de Alvo Molecular , Receptores de Células Precursoras de Linfócitos B/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Células Precursoras de Linfócitos B/efeitos dos fármacos , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Adenina/análogos & derivados , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/metabolismo , Humanos , Piperidinas , Receptores de Células Precursoras de Linfócitos B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia , Proteínas Proto-Oncogênicas c-bcl-6 , Purinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinazolinonas/farmacologia , Receptores de Antígenos de Linfócitos B/antagonistas & inibidores , Receptores de Antígenos de Linfócitos B/metabolismo , Fator de Transcrição STAT5/metabolismoRESUMO
A landmark study has delineated and identified the genetic pathways that drive the natural course of chronic lymphocytic leukaemia (CLL) B cells into Richter's transformation. CLL-related Richter's transformation is a distinct lymphoma, and poses various questions about B-cell ontogeny and relevance of B cell receptor signalling inhibitors.